Data processing: measuring – calibrating – or testing – Measurement system in a specific environment – Biological or biochemical
Reexamination Certificate
1998-12-23
2004-10-05
Marschel, Ardin H. (Department: 1631)
Data processing: measuring, calibrating, or testing
Measurement system in a specific environment
Biological or biochemical
C435S006120, C435S007100, C435S007200, C435S069100, C703S011000
Reexamination Certificate
active
06801859
ABSTRACT:
1. FIELD OF THE INVENTION
The field of this invention relates to methods of identifying common elements or patterns in biological profiles, such as common elements in gene expression profiles, in response to different drug treatments. The invention also relates to the application of these methods to identify ideal drug profiles as well as undesired drug profiles. Further, the invention also relates to the application of these methods to compare profiles from existing drugs to these ideals.
2. BACKGROUND OF THE INVENTION
Within the past decade, several technologies have made it possible to monitor the expression level of a large number of genetic transcripts (see, e.g., Schena et al., 1995,
Science
270:467-470; Lockhart et al., 1996,
Nature Biotechnology
14:1675-1680; Blanchard et al., 1996,
Nature Biotechnology
14:1649; Ashby et al., U.S. Pat. No. 5,569,588, issued Oct. 29, 1996) and proteins (see, e.g., McCormack et al., 1997,
Analytical Chemistry
69:767-776; Chait-BT, 1996,
Nature Biotechnology
14:1544) within a cell at any one time. In organisms for which the complete genome is known, it is possible to analyze the transcripts of all genes within the cell. With other organisms such as human, for which there is an increasing knowledge of the genome, it is possible to simultaneously monitor large numbers of the genes within the cell.
Applications of this technology have included, for example, identification of genes which are up regulated or down regulated in various physiological states, particularly diseased states. Additional uses for transcript arrays have included the analyses of members of signaling pathways, and the identification of targets for various drugs. See, e.g., Friend and Hartwell; U.S. Provisional Patent Application Serial No. 60/039,134, filed Feb. 28, 1997; Stoughton, U.S. patent application Ser. No. 09/099,722, filed Jun. 19, 1998; Stoughton and Friend, U.S. patent application Ser. No. 09/074, 983, filed May 8, 1998; Friend and Hartwell, U.S. Provisional Application Serial No. 60/056,109, filed Aug. 20, 1997; Friend and Hartwell, U.S. application Ser. No. 09/031,216, filed Feb. 26, 1998; Friend and Stoughton, U.S. Provisional Application Serial No. 60/084,742 (filed May 8, 1998). 60,090,004 (filed June 19, 1998), and 60/090,046 (filed Jun. 19, 1998). Such applications are based upon the knowledge that abundances and/or activity levels of cellular constituents (e.g., mRNA species, proteins, and other molecular species within a cell) change in response to perturbations in a cell's biological state, including drug treatment or changes in a protein's activity. Thus, a measurement of such cellular constituents, referred to herein as a “biological profile,” or “profile,” contains a wealth of information about the action of the perturbing agent.
The ability to measure and compare such biological profiles has the potential to be of great human and commercial benefit. For example, it would be of great benefit if an “ideal” or “consensus” response profile could be identified across a large set of cellular constituents, for example all or substantially all of the genetic transcripts of a cell or organism, which characterizes a desired drug activity (e.g., a desired clinical effect). Likewise, it would also be of great benefit, e.g., during the process of drug discovery and design, to provide and compare response profiles of known or existing drugs to such a consensus profile, e.g., to identify promising drug candidates with a particular, desired, therapeutic effect, or to develop theories of why particular individual compounds have clinically superior toxicity profiles. Indeed the basic concept of generating and comparing response profiles to known profiles for the purpose of predicting drug effectiveness and toxicity has been proposed (see, in particular, Fodor, U.S. Pat. No. 5,800,992; Rine and Ashby, 1998, U.S. Pat. No. 5,777,888)
However, the biological profile of any real cell or organism is of tremendously high complexity. Any one perturbing agent may cause a small or large number of cellular constituents to change their abundances and/or activities. Thus, to completely or even mostly characterize the biological response to a particular perturbation it is generally necessary to measure independently the responses of all, or at least most, of the cellular constituents in a cell. Yet, the number of cellular constituents, e.g., for a mammalian cell, is typically on the order of 10
5
. Further, current techniques for quantifying changes in cellular constituents suffer from high rates of measurement errors, including false detections, failures to detect, or inaccurate quantitative determinations. Thus, in practice such analyses of biological profiles is too cumbersome and fraught with technical problems to be practical.
Accordingly, there is a need for methods of analyzing biological profile data which overcome the above limitations in the prior art, and, in particular, which reduce error rates and simplify the structure of changes in the profile data. In particular, there is a need for methods of analyzing biological profile data to derive a simplified “consensus profile,” e.g., for a drug, drug family, or group of related compounds, which characterizes a desired (i.e., ideal) biological effect. Further, there is a need for methods to compare such consensus profiles to the biological profiles of individual drugs or drug candidates.
Discussion or citation of a reference herein shall not be construed as an admission that such reference is prior art to the present invention.
3. SUMMARY OF THE INVENTION
The present invention provides methods for determining a “consensus” profile for a biological response, such as the response of an organism to a group or family of drugs and/or drug candidates. The consensus profile obtained by the methods of this invention represents an ideal, desired activity profile across some standard measurement set such as the cellular constituents of a cell or model organism, or of an organism destined for treatment, e.g., by drug therapy. As such, the consensus profiles of this invention indicate those elements or patterns in a biological profile which the individual compounds have in common. Preferably, such elements or patterns are associated with a particular biological effect—most preferably a particular, desired, therapeutic effect, or “ideal” effect. Accordingly, the present invention also provides methods for obtaining a response profile for a particular compound, such as for a particular drug or drug candidate, and for comparing the response profile of the particular compound to the consensus profile to determine the extent to which the particular compound exhibits a particular, i.e., “ideal,” effect as opposed to “non-ideal” or toxic effects.
Such methods are useful, e.g., in the process of drug discovery or design, for identifying compounds which best meet or satisfy a desired activity profile, as well as for identifying compounds which fall short of a desired activity profile. The methods of the present invention are also useful for analyzing further chemical modifications to lead compounds, or for developing theories of why certain individual compounds have superior toxicity profiles. Finally, because the biological response to a particular compound or compounds will frequently vary between individual organisms, the methods of the present invention are also useful during treatment of an individual, e.g., in a clinical setting, to determine the best compound or combination of compounds to produce a desired therapeutic effect.
The invention is based, at least in part, on the discovery that for any finite set of conditions, including, for example, treatments with different concentrations of related compounds, individual cellular constituents will not vary independently from one another. Rather, sets of cellular constituents will tend to change together, or “co-vary,” under a given set of conditions. Accordingly, the structure of biological profiles can be greatly reduced, without losing accuracy or completeness, by
Friend Stephen H.
He Yudong
Stoughton Roland
Jones Day
Marschel Ardin H.
Rosetta Inpharmatics LLC
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